The overall goal of this application is to investigate the role of insulin-like growth factor 2 receptor (IGF2R) in HIV-associated neurocognitive disorders. The proposed K01 mentored research will critically influence my career development as a new independent investigator and will enable me to fulfill my long-term objective of improving the understanding and treatment of nervous system disorders associated with HIV/AIDS. IGF2R has a crucial function in fetal development and in lysosomal enzyme trafficking but due to the perinatal lethality of the global IGF2R KO mouse, its postnatal role in the whole organism is largely unknown. We have obtained compelling data that indicate that IGF2R is robustly upregulated in activated microglia in HIV encephalitis and that IGF2R functions to promote HIV expression and chemokine production in microglia. These findings suggest previous unknown aspects of IGF2R biology that IGF2R expression is highly regulated in macrophages. Since IGF2R functions to degrade IGF peptides (IGF1 and IGF2) and serum IGF levels are reduced during viral infection, we propose that over-expression of IGF2R in brain macrophages during viral infection and inflammation leads to increased degradation of IGF2 and IGF1, depriving neurons of the necessary trophic factors. We further propose that IGF2R promotes the proviral and proinflammatory activity of microglia, perpetuating the vicious cycle of HIV spread, inflammation and neuronal damage. Specific Aims are (1A): to determine the regulation of IGF2R expression in human CNS in vivo of HIV- and HIV+ individuals with/without encephalitis. (1E3) Determine the regulation of IGF2R expression in human microglia in vitro by inflammatory and infectious stimuli; (2A) to determine the role of IGF2R in HIV infection of microglia in vitro; (2B) to determine the role of IGF2R in microglial inflammatory gene expression; (3A) to generate and characterize macrophage-specific IGF2R KO mice; (3B) to determine the function of IGF2R in HIV infection in vivo and in vitro using the IGF2R KO mice. Upon completion of the proposed studies, I will have attained training in three important areas: neuropathology, virology and in animal studies, all crucial areas of neuroAIDS research. A step-wise progression through the planned experiments combined with the available mentorship, educational programs and the CFAR program at Einstein will ensure successful training towards independence, as well as achievement of the scientific goals outlined in this application. PUBLIC HEALTH RELEVANCE The IGF2R is a protein not previously investigated in brain macrophages. Based on the compelling data demonstrating its new expression during HIV infection, the investigators propose a novel hypothesis that brain macrophages play a central role in maintaining the insulin-like growth factor peptide balance in the brain and that dysregulation of this process during HIV infection can lead to neurodegeneration.